Parkinson's disease (PD) is a common neurological disorder that primarily impairs the basal ganglia motor control circuit. It is caused by degeneration of midbrain dopamine neurons, particularly those in the substantia nigra (SN). The SN has two distinct components: SN pars compacta (SNc) and SN pars reticulata (SNr). The SNc contains the majority of nigrostriatal dopamine projection neurons that are compromised in PD. The SNr is a key output nucleus of the basal ganglia and the majority of its neurons are inhibitory 3-aminobutyric acid (GABA)-containing projection neurons that fire high frequency spikes that are often abnormal in PD. Past research has elucidated many important aspects of basal ganglia physiology and the pathophysiology of PD. However, many critical issues remain unanswered and many important motor abnormalities in PD can not be adequately explained with our current knowledge. NIH's Parkinson's Disease Research Agenda states that "One poorly understood area concerns the consequences of dopamine loss outside the striatum". This application focuses precisely on these poorly understood areas. We hypothesize and our high quality preliminary data support that dendritically released dopamine from nigral dopamine neurons may directly act on SNr GABA output neurons. This ultra-short SNc-SNr dopamine pathway (comparing with the long distance nigro-striato-nigral loop) may provide a fast, direct dopamine control over this key basal ganglia output nucleus. Particularly, a tonic dopamine D1/D5 receptor-mediated direct excitation may aid in SNr GABA output neuron depolarization and regular firing pattern. Loss of this direct dopamine influence after dopamine neuron degeneration may contribute to the abnormalities in SNr GABA output neuron activity in parkinsonian brain and motor deficits. We have designed experiments to test our hypotheses. Multiple state-of-the-art approaches will be used, including single cell reverse transcription (RT)-PCR, quantitative electrophysiology, neurochemistry, neuropharmacology, and immunohistochemistry. Genetically modified mouse lines will also be used to aid in the experiments. New knowledge gained from the proposed projects will advance our understanding of the basal ganglia motor control circuit and the pathophysiology of PD and provide a potential route for therapeutic intervention in movement disorders of basal ganglia origin such as PD. The Public Health Relevance: Parkinson's disease is a common neurological disorder of the basal ganglia motor control neuronal circuit. Using an array of advanced techniques, the proposed experiments seek to delineate a novel, important dopamine pathway that directly influences a key basal ganglia output nucleus. The results will advance our understanding of the pathophysiology of Parkinson's disease and provide a potential route for therapeutic intervention in movement disorders of basal ganglia origin such as Parkinson's disease.